Despite an impressive amount of effort and extensive research, our knowledge of parturition remains scant. Although numerous scientists have investigated “the timing of birth”, we still have a limited understanding of the biological mechanisms that control events initiating delivery, or the availability of methods supposed to prevent these mechanisms from acting inappropriately. A multitude of factors and structures are involved; the myometrium, cervix, placenta and the fetus must act in concert to assure successful delivery. We do know that achievement of a “perfect” contractile force is not the sole factor. Successful delivery is also impacted by subtle differences in pelvic shape or size.

Thyroid hormones are important for normal development of the human central nervous system (CNS). It is well established in children with congenital hypothyroidism that neonatal thyroid hormone deficiency significantly impairs subsequent neurodevelopment. In these children, the period of thyroid hormone insufficiency, which can begin in utero and extend until thyroid status is restored to normal in the neonatal period, determines the severity and type of defect manifested. While prompt and optimal thyroid hormone supplementation, following newborn screening is associated with far improved outcome and near normal development, subtle specific neurodevelopmental differences are still detectable compared to euthyroid controls. Because the particular impairments reflect the exact period of thyroid hormone insufficiency postnatally, as well as during gestation, this implies that brain development is not only thyroid hormone dependent in the neonatal period, but also prior to birth.

Diagnostic ultrasound has an enviable reputation for safety, and the lack of evidence for risk has been one of the key factors which has established it as the pre-eminent imaging method in obstetrics. Ultrasound remains one of very few common diagnostic procedures which may be carried out with little regard to safety. By comparison, all radiographic examinations carry known genetic and somatic risks associated with ionising radiation. Magnetic resonance imaging (MRI) investigations have resulted in several hundred cases of superficial burns, trauma from projectiles, and deaths from malfunctioning pacemakers or displaced metallic inserts. Furthermore, these other modes give rise to biological effects in organs other than those being imaged. For example, a radioisotope lung scan exposes the uterus due to radioactive urine, and scattered x-radiation exposes the ovaries during a chest computed tomography (CT) examination. By comparison, all bio-effects from ultrasound are restricted to the scanned region of tissue.

It is now over half a century since Arthur Hertig first reported vascular pathology in the uterine arteries supplying the placenta in women suffering from preeclampsia. His pioneering histological studies have been validated and extended by many others, leading to the general concept that placental perfusion is compromised in these patients. More recent Doppler ultrasound studies have confirmed reduced intervillous blood flow in vivo, and so gradually a consensus has emerged that the placental lesions associated with preeclampsia arise from a state of chronic hypoxia. Whilst hypoxia may undoubtedly play a significant role in the generation of placental pathology, there is considerable evidence that another feature of the intervillous circulation, namely the constancy of the blood flow, may be a more important factor. In this review we propose that hypoxia-reoxygenation, secondary to intermittent perfusion of the intervillous space, is a more physiological approach to take to understanding the pathophysiology of both normal pregnancies, and those complicated by preeclampsia. We further propose that chronic reduction in placental perfusion alone may lead to fetal growth restriction, and that if the two phenomena are superimposed then preeclampsia with growth restriction will result.

There have been significant strides made over the last two decades in the understanding of the natural history and pathophysiology of fetal thoracic lesions. Largely as a result of advances in prenatal ultrasound we are not only able to offer a tentative diagnosis of these lesions and advise parents about the prognosis but in selected centres offer the possibility of intervention for the most severely affected fetuses. Large gaps do remain in the current state of knowledge, in particular in the inability to predict pulmonary hypoplasia. Fetal surgery for lesions such as congenital cystic adenomatous malformation (CCAM) and pulmonary sequestration sequence (PSS) is still restricted to a very few centres and is reserved for those fetuses with hydrops where there is an extremely poor prognosis. Selection criteria for intervention have been refined over the last decade. Postnatal imaging studies, particularly computed tomography (CT) are essential in the evaluation of these lesions prior to surgical resection.

In the US alone, more than 20 million people suffer from kidney disease. Despite the significant burden of renal disease for the individual and society, treatment options are limited. Over the years, the identification of genes and molecular pathways required for normal renal development has provided insight into our understanding of obvious developmental diseases such as renal agenesis and renal dysplasia. However, many of the genes identified have also been shown to play roles in adult-onset and acquired renal diseases such as focal segmental glomerulosclerosis (scarring of the renal filters). In fact, data suggest that the number of glomeruli and nephrons (filtering units) present in the kidney at birth, which is determined during fetal life, predicts the risk of kidney disease and hypertension later in life; a reduced number is associated with greater risk. To discover novel therapeutic targets and strategies to slow and reverse kidney disease, we must continue to dissect the molecular mechanisms that underlie kidney development.

The length of mammalian pregnancy is tightly regulated to assure the delivery of a newborn mature enough to survive the extra-uterine environment. A successful pregnancy requires near complete relaxation of the uterus for more than ninety-five percent of gestation, overcoming the inherent tendency of the myometrium to contract with stretch. This active and highly regulated process is called myometrial quiescence. It requires not only the near absence of myometrial contractions, but also its refractoriness to contractile agents.

Despite advances in both obstetrics and neonatology the perinatal mortality rate (PNMR) among twins still remains high, estimated as accounting for approximately 10% of all perinatal mortality. Perinatal mortality rates (PNMR) for England and Wales showed a dramatic reduction in perinatal deaths for multiple births over the 1950s to 1980s with a fall from approximately 90 to less than 50 per 1000 births. The Northern Region Perinatal Mortality Survey Steering Group also reported a significant reduction in twin PNMR between 1982 and 1994 from 55.4 to 44.4/1000 births. A similar decrease has also been noted in the Japanese twin population with a reduction in the PNMR between 1980 and 1998 from 91 per 1000 births to 31 per 1000. In Scotland between 1986 and 1990 PNMR for twins was 47 per 1000 approximately 4-5 times the rate in the singleton population. The higher preterm delivery rate in twins, either from spontaneous or induced labour, with its associated problems of prematurity remains the major cause of morbidity and mortality. Other factors, which contribute to the higher PNMR in twins include fetal growth retardation, intra-twin birth weight discordancy, fetal anomalies and problems specific to monochorionic twin gestations.

Ancient Egyptian medical papyri (1550BC) emphasised diagnosis by examination as the cornerstone of the decision to treat or not to treat an ailment. Today the information about the likelihood of diagnosis (and related prognosis) that interventions purport to treat comes from a combination of tests as shown in Figure 1. In addition to easy-to-obtain history (risk factors and symptoms) and examination (signs), current testing includes sophisticated investigations (haematology, biochemistry, radiology, microbiology, etc), which can also be invasive and expensive. Obstetricians routinely incorporate many test results into decision-making concerning management of women at risk of preterm birth, but studies to examine the ways in which even a small number of these tests alter the benefit and harm of treatments are rare.

When an antenatal diagnosis of a fetal anomaly is made, the parents need accurate and clear information regarding prognosis and possible outcomes, to help them make decisions. The healthcare professionals, who are involved in their care and counselling, also need this information.

Antenatal glucocorticoid therapy was pioneered by Liggins & Howie over three decades ago. In a controlled trial of babies delivering before 32 weeks gestation, it was shown that antenatal glucocorticoid treatment reduced the incidence of respiratory distress syndrome (RDS) and significantly lowered neonatal mortality. Synthetic glucocorticoid (sGC) therapy is also associated with reduced risk of neonatal intraventricular haemorrhage, necrotizing entercolitis and hyperbilirubinaemia. The benefit of antenatal glucocorticoid therapy to lung function in the newborn infant has led to routine use in situations of threatened pre-term labour. In 1994, a National Institute of Health Consensus Development Conference recommended antenatal treatment of all women at risk of preterm delivery, between 24 and 34 weeks of gestation, with sGC. Similar statements were issued in Europe, Canada and Australia. However, the NIH Consensus Report highlighted the requirement for further research into the long-term effects of antenatal sGC treatment on development of the brain and other organ systems, and their function after birth.

Proteomics is a new field of research. It has developed rapidly in the last five years and is turning more and more into a mature science with relevance to the clinic. The recent elucidation of the human genome sequence has provided a wealth of useful information but does not provide information on diseases caused by changes at the protein level. Proteomics includes the characterisation and functional analysis of all proteins that are expressed by the genome at a certain moment, under certain conditions. Since expression levels of many proteins strongly depend on complex, but well-balanced regulatory systems, the proteome, unlike the genome, is highly dynamic. This variation depends on the biological function of a cell, but also on signals from its environment. In (bio)medical research it has become increasingly apparent that cellular processes, in particular in disease, are determined by multiple proteins. Hence it is important not to focus on one single gene product (one protein), but to study the complete set of gene products (the proteome). In this way the multi-factorial relations underlying certain diseases may be unravelled potentially identifying therapeutical targets. For many diseases characterisation of the functional proteome is crucial for elucidating alterations in protein expression and modifications. When proteins undergo non-genetically determined alterations such as alternative splicing, or post-translational modifications, e.g. phosphorylation or glycosylation, it may effect their function. Although abnormalities in splicing or post-translational modifications can cause a disease process, they can also be a consequence. An example is that patients with diabetes have a high blood glucose which glycosylates hundreds or even thousands of proteins, including HbA1c which is used to monitor diabetic control.

Ultrasound evaluation of the venous system is now a compulsory part of the haemodynamic assessment of the fetus. Once umbilical venous flow was introduced1,2 and its pulsatile pattern discovered in the compromised fetus,3 other sections of the venous system have been added or explored for possible diagnostic use: the inferior and superior vena cava,4,5 ductus venosus,6,7 hepatic veins,8 pulmonary veins,9,10 and intracranial veins.11-13 The following presentation is not intended to be a complete review of the fetal venous circulation, which is growing by the day, but rather to focus on some central issues with an emphasis on physiologic principles. The reason for this focus is that, as clinicians, we tend to work according to pattern recognition, which is a necessary principle in daily life. However, in the long run as the fetal patient increasingly demands a more dynamic approach to solve the diagnostic riddles, we find ourselves digging deeper into the physiological mechanisms behind ultrasound images and recordings.

Fetal growth restriction (FGR) as a consequence of uteroplacental insufficiency is an important contributor to perinatal death, neonatal morbidity and long-term health problems. Progressive uteroplacental dysfunction leads to placental respiratory failure and fetal hypoxaemia, which triggers compensatory fetal haemodynamic changes including blood flow redistribution towards essential fetal organs (brain, heart and adrenal glands) at the expense of the other body systems. The duration of the compensatory phase is variable, sometimes lasting weeks, and appears not to have deleterious short-term consequences. With further disease progression, the compensatory mechanisms reach their limit and myocardial dysfunction occurs. Once the disease enters this decompensatory phase, the fetus is at high risk of multisystem organ failure and in-utero demise. There is no effective in-utero therapeutic intervention. The main aim of management is to deliver the baby when the risks of antenatal demise and irreversible end-organ dysfunction associated with further prolongation of the pregnancy are greater than the risks from delivery.

Why should obstetricians study maternal cardiac function in normal and complicated pregnancies? Despite our understanding of the importance of disease processes, such as autoimmunity, impaired renal function and long-standing diabetes, on the placenta and thus pregnancy outcome, new data is emerging to suggest that early central cardiovascular adaptions are central to pregnancy success. Furthermore, successful maternal cardiovascular adaptions are a diagnostic test of longer-term cardiovascular health for the mother. The importance of the maternal ‘cardiac pump’ as the “core” of adaptation to pregnancy has increased in the last years. Studies identifying high risk patients by uterine artery Doppler waveforms in the 2nd trimester indicate that high uterine vascular impedance affects a proportion of women (resulting in severe preeclampsia) while the majority remain well. This dichotomy in maternal response is one explanation for the poor screening characteristics of uterine artery Doppler in unselected women. Women destined to develop preeclampsia with abnormal uterine artery Doppler have a latent period before the disease develops. During this phase, the heart adapts to alterations in circulating blood volume, placental implantation, and maternal peripheral vascular impedance. We believe that disordered heart function is an unavoidable part of the disease spectrum of preeclampsia, since it makes many adaptions even in the face of normal pregnancy. In this article we summarise the experience of our group and the published literature concerning maternal cardiac performance in normal and complicated pregnancies. These findings are relevant to modern day clinical practice.

During gametogenesis in mammals, half of the parental chromosomes segregate to each gamete. Upon fertilization of two haploid gametes, the diploid number is restored (Figure 1A). Nondisjunction, malsegregation of the chromosomes during gametogenesis, can give rise to chromosomally unbalanced offspring (trisomies and monosomies) (Figure 1B). Genomic imprinting is an epigenetic phenomenon in which the activity of a gene is reversibly modified depending on the parent of origin. This leads to unequal, monoallelic expression of the maternal and paternal alleles of a diploid locus (Figure 1C). Thus, the normal state of an imprinted locus is an “imbalance”, not of chromosomes, but of the functional genetic content.